Cancer is a progressive disease, occurring in a series of well-defined steps, usually as a consequence of activating or deactivating mutations. These mutations often render proliferating cells self-sufficient for growth, insensitive to growth-inhibitory signals, resistant to programs of terminal differentiation, senescence, or apoptosis, as well as endowing them with unlimited self-renewal capacity, the ability to orchestrate and direct sustained angiogenesis, and the ability to invade and thrive in ectopic tissue environments (see, e.g., Hanahan and Weinberg (2000) Cell 100:57-70).
The mammalian immune response is based on a series of complex cellular interactions, called the “immune network”. Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally hold the opinion that soluble proteins, known as lymphokines, cytokines, or monokines, play a critical role in controlling these cellular interactions.
Lymphokines mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages making up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response.
Recently, a novel IL-7-like cytokine cloned from a murine thymic stromal cell line was identified as thymic stromal lymphoietin (TSLP) (see, e.g., J. E. Sims et al., (2000) J. Exp. Med. 192:671-680; U.S. Ser. No. 09/963,347, filed Sep. 24, 200; and SEQ ID NOs: 1, and 2). The activities of TSLP overlaps with those of IL-7; both stimulate thymocytes and mature T cells and facilitate B lymphopoiesis in cultures of fetal liver and bone marrow lymphocyte precursers. It has also been found that the receptor for TSLP is a heterodimer that consist of an IL-7-R-α chain and a common γ-like receptor chain (see, e.g., Reche et al., (2001) J. of Immunol. 167:336-343; Y. Tonozuka et al., (2001) Cytogenet Cell Genet. 93:23-25; A. Pandey et al., (2000) Nat. Immunol. 1:59-64; L. S. Park et al., (2000) J. Exp. Med. 192:659-670; and SEQ ID NOs: 3, 4, 5, and 6).
Cancer development and metastasis is a multi-step process that involves local neoplasmic growth and invasion followed by dissemination to, and re-establishment at, distant sites. The neoplasm or tumor can consist of transformed cells and infiltration of stromal cells and cells of the immune system. The ability for a tumor to metastasize is the major determinant of cancer-patient mortality. TGF-β, has been implicated in both tumor suppression and progression (see e.g., Oft et al., (2002) Nat. Cell Bio. 4:487-494).
Many of the molecular and cellular mechanisms mediating the relationship between metastasis, innate immunity and cancer remain unsolved. TGF-β expression in tumors facilitates the formation of metastasis. The present invention suggests that TSLP is suppressed by TGF-β.